Pharmaceutical products comprising bisphosphonates

ABSTRACT

A pharmaceutical product comprises a container containing a bisphosphonate solution, in which at least the internal surface of the container comprises a plastic material and in which the container is heat sterilisable, and which is in the form of a ready to use infusion solution, for administration of the bisphosphonate to a patient in need of bisphosphonate treatment.

This invention relates to pharmaceutical products and processes fortheir production, in particular to pharmaceutical products comprisingbisphosphonates and to processes for producing such bisphosphonateproducts.

Bisphosphonates are widely used to inhibit osteoclast activity in avariety of both benign and malignant diseases which involve excessive orinappropriate bone resorption. These pyrophosphate analogs not onlyreduce the occurrence of skeletal related events but they also providepatients with clinical benefit and improve survival. Bisphosphonates areable to prevent bone resorption in vivo; the therapeutic efficacy ofbisphosphonates has been demonstrated in the treatment of osteoporosis,osteopenia, Paget's disease of bone, tumour-induced hypercalcemia (TIH)and, more recently, bone metastases (BM) and multiple myeloma (MM) (forreview see Fleisch H 1997 Bisphosphonates clinical. In Bisphosphonatesin Bone Disease. From the Laboratory to the Patient. Eds: The ParthenonPublishing Group, New York/London pp 68-163).

Customary bisphosphonate dosage forms, e.g. for the treatment of TIH, BMand MM, are intravenous infusion solutions. However, bisphosphonatessolutions, although intrinsically stable, react with di- and polyvalentcations, especially calcium, barium, magnesium, aluminium, boron, andsilicon present in glass to form insoluble precipitates giving rise toturbidity and possible loss of potency, neither of which can betolerated in a pharmaceutical product. Further such precipitates maylead to blockage of blood vessels and thus could cause a thrombosis asserious complication of the medication. Thus long term storage ofbisphosphonate solution formulations in standard glass vials, even ofhydrolytic resistance class I quality is not possible. Also suchsolution in glass products cannot be terminally moist heat sterilized,and must be aseptically filled, because the leaching of cations isaccelerated under the elevated temperature conditions of moist heatsterilization. It has been shown that at pH values acceptable forparenteral delivery, significant amounts of ions are leached out ofcommercially available glass containers (Farm. Vestnik. Vol 54, p. 331(2003)). Consequently, for short term storage of solution in glassproducts it would be necessary to aseptically fill the solutions,although in view of their high chemical stability heat sterilisation ofbisphosphonate solutions is inherently possible. Such aseptic fillingdoes not comply with the currently accepted processing norms, asoutlined in the document no. CPMP/QWP/054/98 corr., “Decision trees forthe selection of sterilisation methods” issued by the European Agencyfor the Evaluation of Medicinal Products (EMEA). The same document alsostates that “the use of an inappropriate heat-labile packaging materialcannot be in itself the sole reason for adoption of aseptic processing”.

Consequently bisphosphonate products for iv infusion are typicallyprovided in the form of solid lyophilisates, which do not show microbialgrowth promoting properties when compared with unpreservedbisphosphonate solutions at physiologically acceptable pHs. Thelyophilisates are made up into the infusion solution with water forinjection or other aqueous solvents shortly before use, e.g. Aredia® andZometa®. In view of the low solubility of the precipitates formed withdivalent and polyvalent cations, even the low levels of alkaline earthmetal impurities present in all commercially available grades of sodiumchloride and saline solutions could result in formation of suchprecipitates when diluting concentrated bisphosphonic acid solutions.

Recently it has been proposed (WO 02/22136, F. H. Faulding & Co Ltd.) toprovide a pharmaceutical product comprising a container containing adiphosphonate in solution, wherein the solution: (a) has a pH of between5 and 8; and (b) is free of organic buffer and polyethylene glycol andwherein the container is a glass container in which the surface incontact with the solution has been pre-treated to protect againstleaching of impurities from the glass by the solution or wherein thecontainer consists of at least one component manufactured from anon-glass material, such as polyethylene, polypropylene andpolymethylpentene. However, WO 02/22136 does not include any teaching asto how, when or if the product is sterilised. Further this referencedoes not give guidance on how to keep the pH value stable over storagetime if highly potent low dosed bisphosphonates as e.g. zoledronic acidis formulated.

It has now been found that bisphosphonate solutions may be formulatedfor long term storage in containers comprising polymeric materials whichcontainers do not chemically interact with the bisphosphonate solutionand which may be conveniently terminally sterilised.

Accordingly the present invention provides a ready-to-use bisphosphonatepharmaceutical product comprising a container containing abisphosphonate solution, in which at least the internal surface of thecontainer comprises a plastic material and in which the container isheat sterilisable.

The products of the present invention are advantageously solutionproducts for parenteral administration which do not requirereconstitution of a lyophilisate prior to use. Conveniently also theproduct may be heat sterilised in situ in the container duringproduction, preferably terminally moist heat sterilised (e.g. by steamthus advantageously obtaining a Sterility Assurance Level of at least10⁻⁶). Additionally, these ready-to-use solutions do not requiredilution prior to use.

The products of the invention may be administered orally, transdermally,or by injection, e.g. subcutaneously, arterially or intravenously. Mostpreferably the products of the invention are administered by intravenousinfusion.

The products of the invention comprise solutions which are ready to use,in which the bisphosphonate is present at a concentration suitable fordirect administration without dilution and as such are referred to as“ready to use solutions”.

Preferably the ready to use solution product is in the form of a unitdose ready to use solution, i.e. contains sufficient bisphosphonate fora single dose treatment. Such unit dose ready to use solution productsfor infusion typically have a volume in the range from about 20 up toabout 500 ml, usually from about 50 to about 250 ml, preferably about100 ml (wherein such volumes may additionally include up to about 20 ml,e.g. preferably about 2 ml, overfill to accommodate for liquid remainingin the container when the ready to use solution is infused to apatient.).

Such ready to use solutions advantageously are brought to aphysiologically acceptable pH value with bases. It has been found thatwith organic bases that have cation complexing properties slight hazesdue to precipitates of the drug substance with cationic impurities ofthe excipients used can be avoided. It further has been found thatcompared to strong inorganic bases as sodium hydroxide, a slightbuffering system is formed in situ with the bisphosphonate itself whichenables more easily adjustment of the desired pH-value and ensuresoptimal stability of the pH value over the whole storage time. The pH ofthe solution is preferably in the region from about pH 4.5 up to aboutpH 8, more preferably in the range from about pH 5.5 up to about pH 7.5,e.g. about pH 6.5 or about pH 6.8 or about pH 7.2. Examples of suitableorganic bases include the sodium or potassium salts of organic acids asacetic acid, citric acid, lactic acid, glutamic acid, tartaric acid,fumaric acid, maleic acid, or malic acid. Furthermore, basic forms ofamino acids may be used, e.g. histidine or arginine. Examples ofsuitable anorganic bases are sodium or potassium phosphate, sodiumhydrogen carbonate or sodium hydroxide. Also mixtures of the abovebases, or mixtures of the bases with their corresponding acids may beused. For example, the formulation may comprise a base, e.g. sodiumcitrate, with an acid, e.g. hydrochloric acid. Preferably the base is asodium or potassium salt. When using potassium salts, the physiologicaltolerability of such formulations however have to be carefully assessed,and it is recommended not to exceed the physiological concentration ofpotassium in blood serum which is approx. 4 milli-moles per litre.

Such ready to use solutions may also typically comprise an isotonisingagent. Preferably the tonicity of the solution is in the range fromabout 250 mOsm/kg up to about 400 mOsm/kg, more preferably from about260 mOsm/kg up to about 350 mOsm/kg, e.g. about 300 mOsm/kg. Examples ofsuitable isotonising agents are: glycerol, polyethylene glycol,propylene glycol, ethanol, cyclodextrins, amino acids, sugars and sugaralcohols including: Glucose, fructose, mannose, mannitol, saccharose,lactose, trehalose, maltose, sorbitol, sodium chloride, sodium nitrate,potassium chloride, urea, ammonium chloride. Preferably the isotonisingagent is a non-ionic isotonising agent, more preferably a sugar, ester,alcohol or polyol. Particularly preferred isotonising agents for use inthe solution pre-concentrate are mannitol, 1,2 propylene glycol,glycerol and sorbitol, of which mannitol is particularly preferred.

It has been found in accordance with the present invention that the useof non-ionic isotonising agents permits easy and reliable analysis, e.g.by ion chromatography, capillary electrophoresis, and high performanceliquid chromatography (HPLC). It has been found, that with reversedphase HPLC using an ion pair reagent (e.g. tetrahexylammonium hydrogensulfate) and a complexation reagent (e.g. ethylendiamintetraacetic acid,EDTA) and the UV detection mode a very low concentration of thebisphophonate and especially of potential by- and degradation productscan be reliably determined. It is highly desirable to be able to detectsuch potential by- and degradation products at the low concentrations atwhich they are present in ready to use solution products. Noderivatization step is necessary. For the ready to use solution productof the present invention a concentrations of 0.04 μg/ml can be reliablyquantified. This corresponds to 0.1% related to the declared dose, whichis the reporting limit, which has to be achieved in order to comply withinternational regulatory guidelines.

In contrast, if one of the customary ionic isotonising agents, e.g.sodium chloride, is used, these interfere with the chromatographicmeasurements to an extent that potential by- and degradation productscannot be reliably quantified.

Thus in particular embodiments the invention includes product as definedabove, in which the isotonising agent is non-ionic:

-   -   i) and in which the product is analysable with a limit of        quantitation for the bisphophonate and its by- and degradation        products of at least 0.1% related to the declared dose,        preferably without applying a derivatization step, and    -   ii) A product as defined above, which is analysable by reversed        phase chromatography with a complexation agent, e.g. EDTA, for        determination of the bisphophonate and its by- and degradation        products with a limit of quantitation of at least 0.1% related        to the declared dose, preferably without applying a        derivatization step.

Thus in a further preferred embodiment the invention provides apharmaceutical product comprising a container containing abisphosphonate solution in the form of a ready to use solution,comprising

a) a unit dose of a bisphosphonate,

b) an organic base, and

c) a non-ionic isotonising agent

in which at least the internal surface of the container comprises atransparent plastic material and in which the filled container isterminally heat sterilisable.

Ready to use solution products may be provided in infusion bags; forinstance as customarily used for infusion of other therapeutic infusionproducts, e.g. plastic infusion bags made of polyvinyl chloride,polyolefine copolymers, a Cryovac® M312 foil (Sealed Air Corporation),Baxter Intravia®, and B.Braun PAB (polypropylene with 10% of styreneethylene-butylenes styrene (SEBS) thermoplastic elastomer) or similarinfusion bags.

The container for the product of the invention may comprise a glasscontainer having a transparent plastic inner lining. Preferably,however, the container is made of plastic material and does not comprisea glass outer shell. Examples of plastic materials which may be usedinclude: polysulfone, polycarbonate, polypropylene, polyethylene (LDPEor HDPE), ethylene/propylene copolymers, polyolefines, acrylic-imidecopolymers, PVC, polyester (e.g. PET, PEN and the like), Teflon, Nylon,acetal (Delrin), polymethylpentene, PVDC, ethylvinylacetate,AN-copolymer etc. The plastic material used for either type of containeris preferably a transparent plastic material, i.e. it is translucent andpermits visual inspection of the contents.

Furthermore the plastic material used is a plastic which is capable ofwithstanding heat sterilisation in the filled and unfilled state,preferably moist heat sterilisation e.g. steam sterilisation orsuperheated water showering sterilisation, at a temperature of at leastabout 110° C. to about 130° C. or higher, e.g. at a temperature of atleast 121° C., e.g. at 121-124° C.

Particularly preferred plastic materials for the container aretransparent cycloolefinic polymers such as Daikyo CZ resin,thermoplastic olefin polymers of amorphous structure (e.g. TOPAS,manufactured by Ticona). Most preferred are Daikyo CZ resin and similarcycloolefinic polymers.

Ready to use products may be provided in plastic or plastic-coatedbottles having a volume from about 20 ml up to about 500 ml, e.g. about100 ml.

Bisphosphonate solutions may also be administered by slow intraveneousinjection of a more concentrated form, e.g. with a concentration in therange from about 0.01 to about 0.5, more usually from about 0.05 up toabout 0.2 mg bisphosphonate/ml. For this purpose the product may also befilled into prefillable syringes that can be terminally moist heatsterilized, e.g. in syringes made of Daikyo CZ resin or similar or ofthermoplastic olefin polymers of amorphous structure (e.g. as sold bySchott under the trade name Schott Top Pac or similar)

Commercially available plastic container materials like the Daikyo CZresin further have a thermal deformation temperature according to ASTMD648 of 123° C., which would narrow down the acceptable sterilizationtemperature to at most 123° C. It has now been found that sterilizationeven at significantly higher temperatures of e.g. up to 130° C., leadneither to measurable deformations of the container nor to impairedcontainer closure integrity.

Preferably the bisphosphonates for use in the invention are the nitrogencontaining bisphosphonates, including those having side chains whichcontain amino groups or especially those having side chains containingnitrogen-containing heterocycles, most especially containing aromaticnitrogen-containing heterocycles.

Examples of suitable bisphosphonates for use in the invention mayinclude the following compounds or a pharmaceutically acceptable saltthereof: 3-amino-1-hydroxypropane-1,1-diphosphonic acid (pamidronicacid), e.g. pamidronate (APD);3-(N,N-dimethylamino)-1-hydroxypropane-1,1-diphosphonic acid, e.g.dimethyl-APD; 4-amino-1-hydroxybutane-1,1-diphosphonic acid (alendronicacid), e.g. alendronate; 1-hydroxy-ethidene-bisphosphonic acid, e.g.etidronate; 1-hydroxy-3-(methylpentylamino)-propylidene-bisphosphonicacid, ibandronic acid, e.g. ibandronate;6-amino-1-hydroxyhexane-1,1-diphosphonic acid, e.g. amino-hexyl-BP;3-(N-methyl-N-n-pentylamino)-1-hydroxypropane-1,1-diphosphonic acid,e.g. methyl-pentyl-APD(=BM 21.0955);1-hydroxy-2-(imidazol-1-yl)ethane-1,1-diphosphonic acid, e.g. zoledronicacid; 1-hydroxy-2-(3-pyridyl)ethane-1,1-diphosphonic acid (risedronicacid), e.g. risedronate, including N-methyl pyridinium salts thereof,for example N-methylpyridinium iodides such as NE-10244 or NE-10446;1-(4-chlorophenylthio)methane-1,1-diphosphonic acid (tiludronic acid),e.g. tiludronate;3-[N-(2-phenylthioethyl)-N-methylamino]-1-hydroxypropane-1,1-diphosphonicacid; 1-hydroxy-3-(pyrrolidin-1-yl)propane-1,1-diphosphonic acid, e.g.EB 1053 (Leo); 1-(N-phenyl-aminothiocarbonyl)methane-1,1-diphosphonicacid, e.g. FR 78844 (Fujisawa);5-benzoyl-3,4-dihydro-2H-pyrazole-3,3-diphosphonic acid tetraethylester, e.g. U-81581 (Upjohn);1-hydroxy-2-(imidazo[1,2-a]pyridin-3-yl)ethane-1,1-diphosphonic acid,e.g. YM 529; and 1,1-dichloromethane-1,1-diphosphonic acid (clodronicacid), e.g. clodronate.

A particularly preferred bisphosphonate for use in the inventioncomprises a compound of Formula I

wherein

-   -   Het is an imidazole, oxazole, isoxazole, oxadiazole, thiazole,        thiadiazole, pyridine, 1,2,3-triazole, 1,2,4-triazole or        benzimidazole radical, which is optionally substituted by alkyl,        alkoxy, halogen, hydroxyl, carboxyl, an amino group optionally        substituted by alkyl or alkanoyl radicals or a benzyl radical        optionally substituted by alkyl, nitro, amino or aminoalkyl;    -   A is a straight-chained or branched, saturated or unsaturated        hydrocarbon moiety containing from 1 to 8 carbon atoms;    -   X is a hydrogen atom, optionally substituted by alkanoyl, or an        amino group optionally substituted by alkyl or alkanoyl        radicals, and    -   R is a hydrogen atom or an alkyl radical,        and the pharmacologically acceptable salts thereof.

Examples of particularly preferred bisphophonates for use in theinvention are:

-   2-(1-Methylimidazol-2-yl)-1-hydroxyethane-1,1-diphosphonic acid;-   2-(1-Benzylimidazol-2-yl)-1-hydroxyethane-1,1-diphosphonic acid;-   2-(1-Methylimidazol-4-yl)-1-hydroxyethane-1,1-diphosphonic acid;-   1-Amino-2-(1-methylimidazol-4-yl)ethane-1,1-diphosphonic acid;-   1-Amino-2-(1-benzylimidazol-4-yl)ethane-1,1-diphosphonic acid;-   2-(1-Methylimidazol-2-yl)ethane-1,1-diphosphonic acid;-   2-(1-Benzylimidazol-2-yl)ethane-1,1-diphosphonic acid;-   2-(Imidazol-1-yl)-1-hydroxyethane-1,1-diphosphonic acid;-   2-(Imidazol-1-yl)ethane-1,1-diphosphonic acid;-   2-(4H-1,2,4-triazol-4-yl)-1-hydroxyethane-1,1-diphosphonic acid;-   2-(Thiazol-2-yl)ethane-1,1-diphosphonic acid;-   2-(Imidazol-2-yl)ethane-1,1-diphosphonic acid;-   2-(2-Methylimidazol-4(5)-yl)ethane-1,1-diphosphonic acid;-   2-(2-Phenylimidazol-4(5)-yl)ethane-1,1-diphosphonic acid;-   2-(4,5-Dimethylimidazol-1-yl)-1-hydroxyethane-1,1-diphosphonic acid,    and-   2-(2-Methylimidazol-4(5)-yl)-1-hydroxyethane-1,1-diphosphonic acid,    and pharmacologically acceptable salts thereof.

More preferred bisphosphonates for use in the invention areDisodium-3-amino-1-hydroxy-propylidene-1,1-bisphosphonate pentahydrate(pamidronic acid) and 2-(imidazol-1yl)-1-hydroxyethane-1,1-diphosphonicacid (zoledronic acid) or pharmacologically acceptable salts thereof.

The most preferred bisphosphonate for use in the invention is2-(imidazol-1yl)-1-hydroxyethane-1,1-diphosphonic acid (zoledronic acid)or a pharmacologically acceptable salt thereof.

Particularly preferred ready to use products are in unit dose form andcomprise from 2 to 10 mg of zoledronic acid or a pharmaceuticallyacceptable salt thereof. Most preferably the zoledronate unit doseproduct comprises an equivalent to 4 mg or 5 mg of anhydrous zoledronicacid, in particular as hereinafter described in the Examples.

Pharmacologically acceptable salts are preferably salts with bases,conveniently metal salts derived from groups Ia, Ib, IIa and IIb of thePeriodic Table of the Elements, including alkali metal salts, e.g.potassium and especially sodium salts, and also ammonium salts withammonia or organic amines.

Especially preferred pharmaceutically acceptable salts are those whereone, two, three or four, in particular two or three, of the acidichydrogens of the bisphosphonic acid are replaced by a pharmaceuticallyacceptable cation, in particular sodium, potassium or ammonium, in firstinstance sodium.

A very preferred group of pharmaceutically acceptable salts ischaracterized by having at least one acidic hydrogen and onepharmaceutically acceptable cation, especially sodium, in each of thephosphonic acid groups.

All the bisphosphonic acid derivatives mentioned above are well knownfrom the literature. This includes their manufacture (see e.g.EP-A-513760, pp. 1348). For example,3-amino-1-hydroxypropane-1,1-diphosphonic acid is prepared as describede.g. in U.S. Pat. No. 3,962,432 as well as the disodium salt as in U.S.Pat. Nos. 4,639,338 and 4,711,880, and1-hydroxy-2-(imidazol-1-yl)ethane-1,1-diphosphonic acid is prepared asdescribed e.g. in U.S. Pat. No. 4,939,130. See also U.S. Pat. Nos.4,777,163 and 4,687,767 and EP 0 275 821 B.

The invention also includes processes for the production of the solutionproducts of the invention, which processes typically comprise a terminalheat sterilization step.

Accordingly in a further aspect the invention comprises a process forthe production of a pharmaceutical product comprising a containercontaining a bisphosphonate solution, in which a bisphosphonate solutionis provided within a container in which at least the internal surface ofthe container comprises a transparent plastic material and in which thecontainer containing the bisphosphonate solution is terminally heatsterilised.

Thus the container containing the bisphosphonate solution is heatsterilized, preferably moist heat sterilised e.g. by saturated steam,steam/air mixtures or superheated water showering sterilisation, at atemperature of at least about 110° C. to about 130° C. or higher, e.g.at a temperature of at least 121° C. or higher, e.g. preferably at about121-124° C. The effective sterilization time depends on the D-value oftest spores in the solution and should be dimensioned that an overallSAL of at least 10⁻⁶, preferably of at least 10⁻¹² is obtained. Theeffective sterilization time (dwell time) may be from about 15 minutesup to about 3 hours, conveniently from about 15 minutes to about 2hours, e.g. preferably about 30 min. Advantageously the heatsterilisation is terminal heat sterilisation, i.e. heat sterilisationwhich is carried out near to or at completion of the production process,after filling of the container with the bisphosphonate solution andpreferably after closure of the container, e.g. with a suitable cap,stopper or other closure. Conveniently standard production equipment forprocessing of glass vials may be used.

Suitable rubber stoppers are those which show only negligible leachingof metal ions like calcium, magnesium, zinc or silica when contactedwith aqueous solutions, e.g. bisphosphonate solutions. Preferredstoppers have a low ash content and are coated on the product side withan impermeable and inert barrier, e.g. made of ETFE, Teflon orfluorinated elastomers. Suitable stoppers are e.g. Daikyo D-777-1,Daikyo D-777-3, Daikyo D-713, Daikyo D-21-7S, all coated on the productside with an ETFE layer, or Helvoet FM259/0 coated with a layer of afluoropolymer (e.g. the Helvoet proprietary material Omniflex orOmniflex plus).

The ready to use bisphosphonate solution may be prepared in bulk anddelivered to the containers; for instance, using the customary artprocedures. The bulk bisphosphonate solution may be in the form of asolution of the free bisphosphonic acid, e.g. zoledronic acid, or in theform of a salt thereof, e.g. the sodium salt. Bulk bisphosphonate saltsolutions may be prepared by dissolving the salt in aqueous media, ormay be prepared in situ in solution by reaction of a dispersion of thefree bisphophonic acid with a base, e.g. neutralisation of the acid withsodium hydroxide to give the mono sodium salt, disodium salt, trisodiumsalt or tetra sodium salt as desired, e.g. disodium pamidronate ordisodium zoledronate.

According to GMP requirements, all container material used forparenteral products are to be subjected to a depyrogenization processensuring an endotoxin reduction of at least 3 log units. Heatdepyrogenisation is customarily used for glass vials. However, plasticvials generally cannot be processed on standard pharmaceutical steriledrug product filling lines, as such containers would not withstand thethermal stress applied in the heat depyrogenization tunnel. Therefore,plastic vials are usually processed without the necessary cleaning anddepyrogenization steps, thus bearing the risk of contamination of theparenteral drug product with foreign matter present in the vials as wellas with Endotoxins that may be dissolved from the vial material surface.Surprisingly it has been found in accordance with the present inventionthat some plastic containers can be processed on standard filling linesfor glass vials, and that provided the washing process is suitablyadjusted an endotoxin reduction by the factor of at least 1000 can bereproducibly obtained.

Thus in addition to the sterilisation step, the containers, inparticular the plastic containers, may be depyrogenised prior to fillingwith bisphosphonate solution. We have found that washing of the plasticvials with water under pressure gives satisfactory depyrogenisation,e.g. reduction in endotoxin concentration by a factor of at least 1000or more, e.g. about 16000-100000. Such a depyrogenisation step ispreferably included within the production processes of the invention.

Alternatively endotoxin-free or substantially endotoxin-free plasticcontainers may be obtained from a supplier and such containers usedwithout need for depyrogenisation.

Furthermore the invention includes processes for preparation of theproducts of the invention as defined above in which reversed phasechromatography with a complexation agent, e.g. EDTA, is used fordetermination of the bisphophonate and its by- and degradation products,advantageously with a limit of quantitation of at least 0.1% related tothe declared dose, preferably without applying a derivatization step.

The particular mode of administration and the dosage for the products ofthe invention may be selected by the attending physician talking intoaccount the particulars of the patient, especially age, weight, lifestyle, activity level, hormonal status (e.g. post-menopausal) and bonemineral density as appropriate. Most preferably, however, thebisphosphonate is administered intravenously.

Normally the dosage is such that a single dose of the bisphosphonateactive ingredient from 0.002-20.0 mg/kg, especially 0.01-10.0 mg/kg, isadministered to a warm-blooded animal weighing approximately 75 kg. Ifdesired, this dose may also be taken in several, optionally equal,partial doses.

“mg/kg” means mg drug per kg body weight of the mammal—including man—tobe treated.

Preferably, the bisphosphonates are administered in doses which are inthe same order of magnitude as those used in the treatment of thediseases classically treated with bisphosphonic acid derivatives, suchas Paget's disease, tumour-induced hypercalcemia or osteoporosis. Inother words, preferably the bisphosphonic acid derivatives areadministered in doses which would likewise be therapeutically effectivein the treatment of Paget's disease, tumour-induced hypercalcaemia orosteoporosis, i.e. preferably they are administered in doses which wouldlikewise effectively inhibit bone resorption.

The following Examples illustrate the invention described hereinbefore.

EXAMPLES Example 1 Zoledronic Acid 4 mg/100 mL

Ingredient Amount [kg] per 1000 L Zoledronic acid monohydrate 0.04264 kgCorresponding to 0.0400 kg zoledronic acid anhydrous Mannitol  51.00 kgSodium citrate  0.240 kg Water for injection Up to 1′015 kg = 1000 L

Approx. 85-95% of the total amount of water for injection is filled intoa stainless steel compounding vessel. The excipients mannitol and sodiumcitrate are added and dissolved under stirring. The drug substancezoledronic acid is added and dissolved under stirring. The preparationis adjusted to the final weight with water for injection. The amount ofsodium citrate neutralizes the zoledronic acid to a pH value of 6.5. Thebulk solution is passed to the filling line and filtered in-line througha filter of 0.2 μm pore size. Washed and dried 100 mL Daikyo CZ plasticvials are filled with 102.0 ml of bulk solution. Sterilized HelvoetFM259/0 Omniflex plus coated stoppers are inserted into the vials, andthe stoppered vials are sealed with aluminium caps. The vials aresterilized with moist heat to obtain a Sterility Assurance Level of10⁻¹², i.e. at 121-123° C. for 30 minutes (effective dwell time).

The product is stable and does not show any sign for degradation eveunder severe stress conditions of 50° C./75% RH and 40° C./75% RH. 40°C./ 50° C./ 75% rel. humidity 75% rel. humidity Test Start 3 months 1month Assay 99.5% 101.4% 98.8% Degradation products, <0.1%  <0.1% <0.1%sum pH-value 6.7 6.6 6.6 Appearance clear, colorless clear, colorlessclear, colorless particle-free solution particle-free solutionparticle-free solution Extractables <0.05 μg/mL <0.05 μg/mL <0.05 μg/mL

Example 2 Zoledronic Acid 5 mg/100 mL

Ingredient Amount [kg] per 1000 L Zoledronic acid monohydrate 0.0533 kgCorresponding to 0.0500 kg zoledronic acid anhydrous Mannitol  49.50 kgSodium citrate  0.300 kg Water for injection Up to 1′014.5 kg = 1000 L

Approx. 85-95% of the total amount of water for injection is filled intoa stainless steel compounding vessel. The excipients mannitol and sodiumcitrate are added and dissolved under stirring. The drug substancezoledronic acid is added and dissolved under stirring. The preparationis adjusted to the final weight with water for injection. The amount ofsodium citrate neutralizes the zoledronic acid to a pH value of 6.5. Thebulk solution is passed to the filling line and filtered in-line througha filter of 0.2 μm pore size. Washed and dried 100 mL Daikyo CZ plasticvials are filled with 102.0 ml of bulk solution. Sterilized HelvoetFM259/0 Omniflex plus coated stoppers are inserted into the vials, andthe stoppered vials are sealed with aluminium caps. The vials aresterilized with moist heat to obtain a Sterility Assurance Level of10⁻¹², i.e. at 121-123° C. for 30 minutes (effective dwell time).

The product is stable and does not show any sign for degradation eveunder severe stress conditions of 50° C./75% RH and 40° C./75% RH. 40°C./75% rel humidity 30° C./70% inverse rel. humidity storage Test Start12 months 6 months Assay 99.8% 100.0% 99.9% Degradation products, <0.1% <0.1% <0.1% sum pH-value  6.6  6.6 6.4 Particulate ≧10 μm 10 10 5matter ≧25 μm  0  0 0 (USP) Appearance clear, colorless clear, colorlessclear, colorless solution solution solution Extractables <0.05 μg/mL<0.05 μg/mL <0.05 μg/mL Heavy Metals Ca   <50 μg/L   <50 μg/L   <50 μg/LMg   <50 μg/L   <50 μg/L   <50 μg/L Al  <100 μg/kg  <100 μg/kg  <100μg/kg Cd  <100 μg/kg  <100 μg/kg  <100 μg/kg Cr  <100 μg/kg  <100 μg/kg <100 μg/kg Cu  <100 μg/kg  <100 μg/kg  <100 μg/kg Fe  <100 μg/kg  <100μg/kg  <100 μg/kg Ti  <100 μg/kg  <100 μg/kg  <100 μg/kg Zn  <100 μg/kg <100 μg/kg  <100 μg/kg

Example 3 Adjustment of pH Value in Zoledronic Acid Formulations withDifferent Bases

533.1 mg of zoledronic acid monohydrate (equivalent to 500 mg ofzoledronic acid) and 480.0 g of mannitol are added to 7520 g of waterfor injection and stirred until a clear solution with a total weight of8000 g is obtained. Each 800 g of this solution (equivalent to 50 mg ofzoledronic acid) are titrated with

(a) a solution of 0.500 g/100 mL trisodium citrate dihydrate in waterfor injection

(b) a solution of 0.500 g/100 mL anhydrous sodium acetate in water forinjection

(c) a solution of 0.500 g/100 mL disodium tartrate dihydrate in waterfor injection

(d) a solution of 0.500 g/100 mL trisodium phosphate hexahydrate inwater for injection

(e) a solution of 0.400 g/100 mL sodium hydroxide in water for injection

The pH value after each addition of 200 μL of base solution is recordedpotentiometrically. The data show that due to the pKa values ofzoledronic acid of 5.9 and 8.28, a steep increase of the pH value in thephysiologically most preferred pH range of pH 6 to 7.5 is seen whenusing sodium hydroxide as base. Compared to that with sodium phosphateand sodium citrate the dissociation of the zoledronic acid acidic groupsis slightly buffered, and therefore the desired pH value of usually pH6.0-7.5 easily can be adjusted.

Example 4 Zoledronic Acid 5 mg/100 mL Formulated with Trisodium Citrateat Different pH Values

Formulation 4A: Formulation 4B: Formulation 4C: Ingredient pH 6.0 pH 6.5pH 7.0 Zoledronic acid 53.3 mg 53.3 mg 53.3 mg monohydrate Correspondingto 50 mg zoledronic acid anhydrous Mannitol 50.0 g 49.5 g 47.0 gTrisodium citrate dihydrate 0.115 g 0.300 g 1.00 g Water for injectionUp to 1.00 L Up to 1.00 L Up to 1.00 L

Example 5 Zoledronic Acid 5 mg/100 mL Formulated with TrisodiumPhosphate at Different pH Values

Formulation Formulation Formulation Formulation Ingredient 5A: pH 6.05B: pH 6.5 5C: pH 7.0 5D: pH 7.5 Zoledronic acid 53.3 mg 53.3 mg 53.3 mg53.3 mg monohydrate Corresponding to 50 mg zoledronic acid anhydrousMannitol 50.0 g 50.0 g 50.0 g 50.0 g Trisodium phosphate 0.038 g 0.050 g0.065 g 0.085 g hexahydrate Water for injection Up to 1.00 L Up to 1.00L Up to 1.00 L Up to 1.00 L

Example 6 Zoledronic Acid 5 mg/100 mL Formulated with Sodium Acetate atDifferent pH Values

Formulation 6A: Formulation 6B: Ingredient pH 5.5 pH 6.0 Zoledronic acid53.3 mg 53.3 mg monohydrate Corresponding to 50 mg zoledronic acidanhydrous Mannitol 49.5 g 49.0 g Sodium acetate anhydrous 0.125 g 0.500g Water for injection Up to 1.00 L Up to 1.00 L

Example 7 Zoledronic Acid 4 mL/100 mL

Ingredient Amount [kg] per 1000 L Zoledronic acid monohydrate 0.04264 kgCorresponding to 0.0400 kg zoledronic acid anhydrous Mannitol  51.00 kgSodium citrate  0.240 kg Water for injection Up to 1′015 kg = 1000 L

Approx. 85-95% of the total amount of water for injection are filledinto a stainless steel compounding vessel. The excipients mannitol andsodium citrate are added and dissolved under stirring. The drugsubstance zoledronic acid is added and dissolved under stirring. Thepreparation is adjusted to the final weight with water for injection.The bulk solution is passed to the filling line and filter in-linethrough a filter of 0.2 μm pore size. Empty plastic infusion bags madeof a Cryovac® M312 foil (Sealed Air Corporation), Baxter Intravia®, andB.Braun PAB® (polypropylene based foil) are filled with each 102.0 ml ofbulk solution. The bags are hermetically sealed. The bags are sterilizedwith moist heat under a supportive pressure of at least 100 mbar abovethe water vapour pressure at the chamber temperature (superheated watershowering or steam/air mixture) to obtain a Sterility Assurance Level of10⁻¹², i.e. at 121-123° C. for 30 minutes (effective dwell time).

Example 8 Zoledronic Acid 5 mg/100 mL

Ingredient Amount [g] per 1 L Zoledronic acid monohydrate 0.0533 gCorresponding to 0.0500 g zoledronic acid anhydrous Sorbitol crystalline50.0 g Sodium citrate 0.300 g Water for injection Up to 1.00 L

Approx. 800 g of water for injection are filled into the compoundingvessel. The excipients Sorbitol and sodium citrate are added anddissolved under stirring. The drug substance zoledronic acid is addedand dissolved under stirring. The preparation is adjusted to the finalvolume with water for injection. The solution is filtered into the vialsthrough a filter of 0.2 μm pore size. Washed and dried Daikyo CZ plasticvials are filled with the bulk solution. Sterilized Helvoet FM259/0Omniflex plus coated stoppers are inserted into the vials, and thestoppered vials are sealed with aluminium caps. The vials are sterilizedwith moist heat.

As can be seen from the table below, the formulation is stable evenafter severe heat intake of 121° C./60 minutes after sterilization (121°C./60 min Test prior to sterilization effective dwel time) Colorcolorless colorless Clarity clear, particle free clear, particle freepH-value 6.3 6.1No change in assay value is observed, and prior as well as aftersterilization no degradation products at levels above the limit ofdetection could be found.

Example 9 Zoledronic Acid 5 mg/100 mL

Ingredient Amount [g] per 1 L Zoledronic acid monohydrate 0.0533 gCorresponding to 0.0500 g zoledronic acid anhydrous Glycerol water free22.5 g Sodium citrate 0.300 g Water for injection Up to 1.00 L

Approx. 800 g of water for injection are filled into the compoundingvessel. The excipients glycerol and sodium citrate are added anddissolved under stirring. The drug substance zoledronic acid is addedand dissolved under stirring. The preparation is adjusted to the finalvolume with water for injection. The solution is filtered into the vialsthrough a filter of 0.2 μm pore size. Washed and dried Daikyo CZ plasticvials are filled with the bulk solution. Sterilized Helvoet FM259/0Omniflex plus coated stoppers are inserted into the vials, and thestoppered vials are sealed with aluminium caps. The vials are sterilizedwith moist heat.

As can be seen from the table below, the formulation is stable evenafter severe heat intake of 121° C./60 minutes after sterilization (121°C./60 min Test prior to sterilization effective dwell time) Colorcolorless colorless Clarity clear, particle free clear, particle freepH-value 6.4 6.2No change in assay value is observed, and prior as well as aftersterilization no degradation products at levels above the limit ofdetection could be found.

Example 10 Zoledronic Acid 5 mg/100 mL

Ingredient Amount [g] per 1 L Zoledronic acid monohydrate 0.0533 gCorresponding to 0.0500 g zoledronic acid anhydrous 1,2 propylene glycol19.0 g Sodium citrate 0.300 g Water for injection Up to 1.00 L

Approx. 800 g of water for injection are filled into the compoundingvessel. The excipients Propylene glycol and sodium citrate are added anddissolved under stirring. The drug substance zoledronic acid is addedand dissolved under stirring. The preparation is adjusted to the finalvolume with water for injection. The solution is filtered into the vialsthrough a filter of 0.2 μm pore size. Washed and dried Daikyo CZ plasticvials are filled with the bulk solution. Sterilized Helvoet FM259/0Omniflex plus coated stoppers are inserted into the vials, and thestoppered vials are sealed with aluminium caps. The vials are sterilizedwith moist heat.

As can be seen from the table below, the formulation is stable evenafter severe heat intake of 121° C./60 minutes after sterilization (121°C./60 min Test prior to sterilization effective dwell time) Colorcolorless colorless Clarity clear, particle free clear, particle freepH-value 6.4 6.3No change in assay value is observed, and prior as well as aftersterilization no degradation products at levels above the limit ofdetection could be found.

Example 11 Washing of Vials/Endotoxin Removal

The plastic vials are processed on a conventional integrated automaticliquid filling processing line. Washing is performed in a conventionalrotary vial washing machine (e.g. Bausch&Stroebel FAU 6000 or Bosch RRU2020) as used for glass vials. The vials are put on the feeding belt ofthe washing machine. In a first instance the vials are submerged in abath with hot water and treated by sonication. After that the vials aretransported to the rotary washing station and are inverted. Cleaning isaccomplished by a programmed process of air and water flushing throughnozzles inserted into the vials. The vials are first washed withrecycled hot Water for Injections (>70° C.), blown out with filteredair, then washed again with fresh hot Water for Injections and blown outwith filtered air. Following washing, the vials are inverted again totheir normal position, and then transferred by the conveyor to the beltof the hot air tunnel, where they are dried at 110° C. On aBausch&Stroebel FAU 6000 washing machine, a washing speed of 84vials/min is suitable.

On a Bosch RRU 2020, a suitable washing speed is at a machine setting of5.8-6.5 scale units.

The efficiency of this process has been assessed by comparison of theendotoxin load of endotoxin-spiked vials prior and after the routinewashing process. The results show more than 3 log reduction of theendotoxin challenge, i.e. the requirement of more than a 3 log reductionwas met at each position tested during the washing process.

Endotoxin Recovery from Treated Vials

Endotoxin is spiked into the plastic vials and dried. The endotoxinspike recovery from five non washed vials is determined in duplicate(spike controls). The spike is 8538 EU (IU) per vial, i.e. the meanvalue of the results minus two times the standard deviation.

Three qualification runs are performed. In each run 10 vials spiked withendotoxin are distributed into one batch of un-spiked vials and arewashed in the washing machine.

Results of Endotoxin Recovery: EU (IU)/vial Run 1 Run 2 Run 3 Vial 1<0.63 <0.63 1.57 Vial 2 <0.63 <0.63 <0.63 Vial 3 <0.63 <0.63 <0.63 Vial4 0.64 <0.63 <0.63 Vial 5 <0.63 <0.63 <0.63 Vial 6 <0.63 <0.63 <0.63Vial 7 <0.63 <0.63 <0.63 Vial 8 <0.63 <0.63 <0.63 Vial 9 <0.63 <0.63<0.63 Vial 10 <0.63 <0.63 <0.63

In all vials tested an endotoxin reduction of at least a factor 1000 isshown.

Example 12 Sterilization of Zoledronic Acid 5 mg/100 mL

Studies have shown that the solution for infusion is chemically andphysically stable during autoclaving. Upon sterilisation of up to 150minutes at ≧121° C. no degradation of the drug substance could beobserved (please see results in the table below). This heat resistanceallows an overkill sterilisation cycle yielding a sterility assurancelevel (SAL) of at least 10⁻¹².

Based on the spore reduction kinetics, expressed in the decimalreduction value (D-value) of Geobacillus stearothermophilus spores inthe Zoledronic acid 5 mg/100 mL drug product solution, a sterilisationtime (dwell time) of 30 minutes was derived to obtain the desired sporereduction rate. The chosen sterilization procedure is in line with therequirements of Ph. Bur. and USP. Stability of Zoledronic acid 5 mg/100ml upon prolonged sterilization times Autoclaved for Autoclaved forAutoclaved 30 additional additional 2 times 60 min/ Parameterminutes/121° C. 60 min/124° C. 124° C. Overall dwell 30 min. 90 min. 150min. time at >121° C. Appearance of 100 ml colourless 100 ml colourless100 ml colourless the container plastic vials, grey plastic vials, greyplastic vials, grey rubber-stopper, rubber-stopper, rubber-stopper,aluminium cap with aluminium cap with aluminium cap with plastic flipcomponent plastic flip component plastic flip component Appearance ofclear, colourless clear, colourless clear, colourless the solutionsolution solution solution Absorbance of 0.00 0.00 0.00 the solution* pHvalue 6.6 6.6 6.6 Particulate matter: >25 μm 0 (USP) 0 (USP) 0 (USP) 3(Ph. Eur.) 0 (Ph. Eur.) 7 (Ph. Eur.) >10 μm 20 (USP) 10 (USP) 0 (USP) 13(Ph. Eur). 3 (Ph. Eur). 10 (Ph. Eur). Degradation <0.1% <0.1% <0.1%products Assay of 98.7% 99.6% 99.3% zoledronic acid Bacterial <0.025 EU(IU)/mL <0.025 EU (IU)/mL <0.025 EU (IU)/mL endotoxins Container/Complies: no unit out Complies: no unit out Complies: no unit outclosure of 40 vials tested shows of 40 vials tested shows of 40 vialstested shows tightness by sign for dye ingress sign for dye ingress signfor dye ingress dye intrusion

Compared to multiple sterilization in glass vials, no increase inparticulate matter is detected. The formulation is stable even after atotal sterilization time of 150 minutes at >121° C.

Example 13 Evaluation of Plastic Vials Under Worst Case SterilizationConditions

During processing, the vials are exposed to dry heat (drying afterwashing) of up to 120° C. and moist heat (during autoclaving) of up to124° C. To assess any potential risk for damage of the vial and thecontainer closure integrity, a heat resistance study has been performed.

20 empty vials as used for Example 2 are subjected to dry heat at 125°C. for 10 hours, which is above the temperature of a drying processwhich is normally set to 100-120° C. Prior and after heat treatment theinner diameter and the ovality of the vial neck were determined as thesedimensions are considered to be the most critical parameters for vialtightness. A negligible reduction of the inner diameter of the vial neckby 0.03 mm (range 0.02-0.05 mm) is observed. The apparent ovality, givenas the difference of two perpendicular diameters of the vial openingdivided by the sum of these diameters, remained unchanged and is 0.18%in the selected samples (prior to treatment: range 0.05-0.45%; aftertreatment: range 0.00-0.50%).

Vials from Example 2 are subjected to a worst case steam sterilizationcycle of 60 minutes in saturated steam at 124.5° C., which is above thethermal deformation temperature of the vial of 123° C. according to ASTMD648). Supporting overpressure is not applied during the sterilisationphase. Sterilized as well as not-sterilized reference samples are testedfor dimensional changes as well as for tightness by dye intrusion andweight loss.

Results of the evaluation of vials in worst case sterilization Aftersterilization Before sterilization (124.5° C./60 min) Weight loss (2weeks, 40° C.), 21 mg 22 mg n = 20 (range: 20-22 mm) (range: 21-23 mm)Inner diameter of vial mouth, 22.0 mm 22.1 mm n = 20 (range: 21.96-22.04mm) (range: 22.09-22.18 mm) Apparent ovality of inner 0.11% 0.20%diameter of vial mouth, n = 8 (range: 0.00-0.23%) (range: 0.00-0.41%)Container closure tightness by tight tight dye intrusion, n = 40

Sterilization at worst case conditions does not have any detectableinfluence on vial tightness as expressed by weight loss and resistanceto dye intrusion. A very slight change is observed in the inner diameterof the vial mouth, but the values are within the specifications of22.0+/−0.2 mm.

Example 14 Analytics of Zoledronic Acid 4 mg/100 mL Solutions

Column Luna, RP-C18 (2), 5 μm (in steel), Phenomenex Length 250 mm,internal diameter 4.6 mm, or equivalent column Stock solution EDTAAccurately weigh to 0.001 g 0.365 g of EDTA into a 100 ml volumetricflask, dissolve with 5 ml 2 M NaOH and fill up to the mark with waterMobile phase Accurately weigh to 0.1 g 6.2 g of disodium hydrogenphosphate dihydrate (35 mM) and 4.5 g of tetrahexyl- ammonium hydrogensulfate (10 mM) into a flask, add 900 ml of water, 100 ml ofacetonitrile dissolve and add 2 ml of EDTA stock solution and mixthoroughly. Adjust the pH to 7.9 with 2 M sodium hydroxide solution.Flow rate 1.2 ml/min Detection 215 nm Temperature 30° C. Injectionvolume 160 μl Run time Approx. 80 min Important remarks PEEK capillariesare recommended at least between column and detector In order to avoidadsorption on glass surfaces use plastic auto sampler vials and pasteurpipettes made from plastic. Reference solutions have to be prepared withvolumetric flasks of frequently used glassware or of plastic and storedin plastic flasks.

Example 15 Ready-to Use Formulations of Pamidronic Acid

Composition per unit dose pack of 100.0 mL equivalent to 101.5 g: 15mg/100 mL 30 mg/100 mL 60 mg/100 mL 90 mg/100 mL Ingredient strengthstrength strength strength Pamidronic acid disodium salt 19.79 mg 39.58mg 79.16 mg 118.74 mg pentahydrate equivalent to pamidronic acid 15 mg30 mg 60 mg 90 mg Citric acid Ph. Eur. approx. 1.5 mg approx. 3 mgapprox. 6 mg approx. 9 mg up to pH 6.5 Mannitol Ph. Eur. 5185 mg 5170 mg5140 mg 5110 mg Water for injection 96.29 g 96.28 g 96.27 g 96.26 g

Based on the basic composition of one dosage form unit given in thetable above, the amount needed for the batch to be manufactured iscalculated. A typical batch size is approx. 5 L for a lab scale batch,100 L for a pilot scale batch and 1000 L for a production scale batch.

Approx. 85-95% of the total amount of water for injection are filledinto a stainless steel compounding vessel. Mannitol is added anddissolved under stirring. The drug substance pamidrionic acid disodiumsalt pentahydrate is added and dissolved under stirring. The pH value isadjusted with a 5% solution of citric acid in water for injection. Thepreparation is adjusted to the final weigh with water for injection. Thebulk solution is passed to the filling line and filter in-line through afilter of 0.2 μm pore size. Washed and dried Daikyo CZ 100 mL plasticvials are filled with each 102 mL of the bulk solution. SterilizedHelvoet FM259/0 Omniflex plus coated stoppers are inserted into thevials, and the stoppered vials are sealed with aluminium caps. The vialsare sterilized with moist heat at >121° C. for at least 15 minutes(effective dwell time).

Example 16 Ready-to Use Formulations of Pamidronic Acid

Composition per unit dose pack of 100.0 mL equivalent to 101.5 g: 15mg/100 mL 30 mg/100 mL 60 mg/100 mL 90 mg/100 mL Ingredient strengthstrength strength strength Pamidronic acid disodium salt 19.79 mg 39.58mg 79.16 mg 118.74 mg pentahydrate equivalent to pamidronic acid 15 mg30 mg 60 mg 90 mg Phosphoric acid 85% approx. 2.35 mg approx. 4.7 mgapprox. 9.4 mg approx. 14.1 mg up to pH 6.3 Mannitol Ph. Eur. 5185 mg5170 mg 5140 mg 5110 mg Water for injection 96.29 g 96.28 g 96.27 g96.26 g

Based on the basic composition of one dosage form unit given in thetable above, the amount needed for the batch to be manufactured iscalculated. A typical batch size is approx. 5 L for a lab scale batch,100 L for a pilot scale batch and 1000 L for a product-ion scale batch.

Approx. 85-95% of the total amount of water for injection are filledinto a stainless steel compounding vessel. Mannitol is added anddissolved under stirring. The drug substance pamidrionic acid disodiumsalt pentahydrate is added and dissolved under stirring. The pH value ofpH 6.3 is adjusted with a 5% solution of phosphoric acid in water forinjection. The preparation is adjusted to the final weight with waterfor injection. The bulk solution is passed to the filling line andfilter in-line through a filter of 0.2 μm pore size. Washed and driedDaikyo CZ 100 mL plastic vials are filled with each 102 mL of the bulksolution. Sterilized Helvoet FM259/0 Omniflex plus coated stoppers areinserted into the vials, and the stoppered vials are sealed withaluminium caps. The vials are sterilized with moist heat at >121° C. forat least 15 minutes (effective dwell time).

Example 17 Ready-to Use Formulations of Pamidronic Acid

Composition per unit dose pack of 100.0 mL equivalent to 101.5 g: 15mg/100 mL 30 mg/100 mL 60 mg/100 mL 90 mg/100 mL Ingredient strengthstrength strength strength Pamidronic acid disodium salt 19.79 mg 39.58mg 79.16 mg 118.74 mg pentahydrate equivalent to pamidronic acid 15 mg30 mg 60 mg 90 mg Acetic acid glacial Ph. Eur. approx. 1.25 mg approx.2.5 mg approx. 5.0 mg approx. 7.5 mg up to pH 6.5 Mannitol Ph. Eur. 5185mg 5170 mg 5140 mg 5110 mg Water for injection 96.29 g 96.28 g 96.27 g96.26 g

Based on the basic composition of one dosage form unit given in thetable above, the amount needed for the batch to be manufactured iscalculated. A typical batch size is approx. 5 L for a lab scale batch,100 L for a pilot scale batch and 1000 L for a production scale batch.

Approx. 85-95% of the total amount of water for injection are filledinto a stainless steel compounding vessel. Mannitol is added anddissolved under stirring. The drug substance pamidrionic acid disodiumsalt pentahydrate is added and dissolved under stirring. The pH value ofpH 6.3 is adjusted with a 5% solution of acetic acid in water forinjection. The preparation is adjusted to the final weight with waterfor injection. The bulk solution is passed to the filling line andfilter in-line through a filter of 0.2 μm pore size. Washed and driedDaikyo CZ 100 mL plastic vials are filled with each 102 mL of the bulksolution. Sterilized Helvoet FM259/0 Omniflex plus coated stoppers areinserted into the vials, and the stoppered vials are sealed withaluminium caps. The vials are sterilized with moist heat at >121° C. forat least 15 minutes (effective dwell time).

Example 18 Ready-to Use Formulations of Pamidronic Acid

Composition per unit dose pack of 100.0 mL equivalent to 101.5 g: 15mg/100 mL 30 mg/100 mL 60 mg/100 mL 90 mg/100 mL Ingredient strengthstrength strength strength Pamidronic acid disodium salt 19.79 mg 39.58mg 79.16 mg 118.74 mg pentahydrate equivalent to pamidronic acid 15 mg30 mg 60 mg 90 mg Lactic acid Ph. Eur. approx. 2.5 mg approx. 5.0 mgapprox. 10.0 mg approx. 15.0 mg up to pH 6.5 Mannitol Ph. Eur. 5185 mg5170 mg 5140 mg 5110 mg Water for injection 96.29 g 96.28 g 96.27 g96.26 g

Based on the basic composition of one dosage form unit given in thetable above, the amount needed for the batch to be manufactured iscalculated. A typical batch size is approx. 5 L for a lab scale batch,100 L for a pilot scale batch and 1000 L for a production scale batch.

Approx. 85-95% of the total amount of water for injection are filledinto a stainless steel compounding vessel. Mannitol is added anddissolved under stirring. The drug substance pamidrionic acid disodiumsalt pentahydrate is added and dissolved under stirring. The pH value ofpH 6.3 is adjusted with a 5% solution of lactic acid in water forinjection. The preparation is adjusted to the final weight with waterfor injection. The bulk solution is passed to the filling line andfilter in-line through a filter of 0.2 μm pore size. Washed and driedDaikyo CZ 100 mL plastic vials are filled with each 102 mL of the bulksolution. Sterilized Helvoet FM259/0 Omniflex plus coated stoppers areinserted into the vials, and the stoppered vials are sealed withaluminium caps. The vials are sterilized with moist heat at >121° C. forat least 15 minutes (effective dwell time).

Example 19 Ready-to Use Formulations of Pamidronic Acid

Composition per unit dose pack of 100.0 mL equivalent to 101.5 g: 15mg/100 mL 30 mg/100 mL 60 mg/100 mL 90 mg/100 mL Ingredient strengthstrength strength strength Pamidronic acid disodium salt 19.79 mg 39.58mg 79.16 mg 118.74 mg pentahydrate equivalent to pamidronic acid 15 mg30 mg 60 mg 90 mg Tartaric acid Ph. Eur. approx. 1.5 mg approx. 3.0 mgapprox. 6.0 mg approx. 9.0 mg up to pH 6.5 Mannitol Ph. Eur. 5185 mg5170 mg 5140 mg 5110 mg Water for injection 96.29 g 96.28 g 96.27 g96.26 g

Based on the basic composition of one dosage form unit given in thetable above, the amount needed for the batch to be manufactured iscalculated. A typical batch size is approx. 5 L for a lab scale batch,100 L for a pilot scale batch and 1000 L for a production scale batch.

Approx. 85-95% of the total amount of water for injection are filledinto a stainless steel compounding vessel. Mannitol is added anddissolved under stirring. The drug substance pamidrionic acid disodiumsalt pentahydrate is added and dissolved under stirring. The pH value ofpH 6.3 is adjusted with a 5% solution of tartaric acid in water forinjection. The preparation is adjusted to the final weight with waterfor injection. The bulk solution is passed to the filling line andfilter in-line through a filter of 0.2 μm pore size. Washed and driedDaikyo CZ 100 mL plastic vials are filled with each 102 mL of the bulksolution. Sterilized Helvoet FM259/0 Omniflex plus coated stoppers areinserted into the vials, and the stoppered vials are sealed withaluminium caps. The vials are sterilized with moist heat at >121° C. forat least 15 minutes (effective dwell time).

1. A pharmaceutical product in the form of a ready to use solutioncomprising a container containing a bisphosphonate solution, in which atleast the internal surface of the container comprises a plastic materialand in which the container is heat sterilisable.
 2. A product accordingto claim 1, in unit dose form having a volume of from about 20 ml up toabout 500 ml.
 3. A product according to claim 1 or comprising abuffering agent, preferably a basic buffering agent, more preferably anorganic base buffering agent.
 4. A product according to claim 3,adjusted with an organic base to a physiologically acceptable pH valueof pH 5.5-8.0, preferably pH 6.0-7.5, most preferably pH 6.5.
 5. Aproduct according to claim 4, in which the organic base is sodiumcitrate
 6. A product according to claim 4, in which the organic base issodium acetate
 7. A product according to claim 4, in which the base issodium or potassium phosphate
 8. A product according to claim 4, inwhich the base is sodium or potassium hydroxide
 9. A product accordingto claim 1, comprising an isotonising agent, preferably a non-ionicisotonising agent, more preferably a sugar, ester or alcohol, e.g.mannitol, 1,2 propylene glycol, glycerol and sorbitol, of which mannitolis particularly preferred.
 10. A product according to claim 9, in whichthe isotonising agent is a non-ionic isotonising agent and which isanalysable with a limit of quantitation for the bisphophonate and itsby- and degradation products of at least 0.1% related to the declareddose, preferably without applying a derivatization step.
 11. A productaccording to claim 10, which is analysable by reversed phasechromatography with a complexation agent, e.g. EDTA, for determinationof the bisphophonate and its by- and degradation products.
 12. Apharmaceutical product comprising a container containing abisphosphonate solution in the form of a ready to use solution,comprising a) a unit dose of a bisphosphonate; b) an organic basebuffering agent, and c) a non-ionic isotonising agent in which at leastthe internal surface of the container comprises a plastic material andin which the filled container is terminally heat sterilisable.
 13. Aproduct according to claim 1, in which the container is a prefillableplastic syringe.
 14. A product according to claim 1, in which theplastic material is transparent.
 15. A product according to claim 1, inwhich the plastic material is a cycloolefinic polymer.
 16. A productaccording to claim 15, in which the plastic material is is Daikyo CZresin or a similar cycloolefinic polymer
 17. A product according toclaim 15, in which the plastic material is a Ticona TOPAS Polymer.
 18. Aproduct according to claim 15, in which the plastic material is a SchottTopPac vial or syringe.
 19. A product according to claim 1 in which thecontainer is an infusion bag.
 20. A product according to claim 19, inwhich the infusion bag is made of polypropylene, polypropylene/Kratonblend, a multilayer bag with polypropylene or polyethylene at theproduct contacting side.
 21. A product according to claim 19, in whichthe infusion bag is a Baxter Intravia container.
 22. A product accordingto claim 19, in which the infusion bag is a Braun Ecoflac container. 23.A product according to claim 19, in which the infusion bag is a BraunPAB container.
 24. A product according to claim 19, in which theinfusion bag is made of a Cryovac M312 foil.
 25. A product according toclaim 1 in which the container is made by the Blow/Fill/Seal technologyand the container material is selected from Polyethylene orPolypropylene.
 26. A product according to claim 25 in which thecontainer is made by the Blow/Fill/Seal technology and the containermaterial is Polypropylene.
 27. A product according to claim 25, in whichthe container is made by the Blow/Fill/Seal technology and the containermaterial is Rexene 32M2 polypropylene.
 28. A product according to claim1, in which the bisphosphonate is an N-bisphosphonate or apharmacologically acceptable salt thereof.
 29. A product according toclaim 28 in which the bisphosphonate is2-(imidazol-1yl)-1-hydroxyethane-1,1-diphosphonic acid (zoledronic acid)or a pharmacologically acceptable salt thereof.
 30. A product accordingto claim 28 in which the bisphosphonate isDisodium-3-amino-1-hydroxy-propylidene-1,1-bisphosphonate pentahydrate(pamidronic acid) or a pharmacologically acceptable salt thereof.
 31. Aprocess for the production of a ready to use bisphosphonatepharmaceutical product comprising a container containing abisphosphonate solution, in which a bisphosphonate solution is providedwithin a container in which at least the internal surface of thecontainer comprises a transparent plastic material and in which thecontainer is heat sterilised, preferably moist heat sterilised.
 32. Aprocess according to claim 31, in which the container is terminally heatsterilized.
 33. A process according to claim 31, in which heatsterilization is at a temperature of at least about 110° C. to about130° C. or higher, e.g. at a temperature of at least 121° C. or higher,e.g. preferably at about 121-124° C.
 34. A process according to claim31, in which the dwell time is from about 15 minutes up to about 3hours, conveniently from about 15 minutes to about 2 hours, e.g.preferably about 30 min.
 35. A process according to claim 31, in whichautoclaving conditions are applied to obtain a sterility assurance levelof at least 10⁻⁶, e.g. by autoclaving (dwell time) at >121° C. for atleast the 8-fold time of the D₁₂₁ value of the solution.
 36. A processaccording to claim 31, in which autoclaving conditions are applied toobtain a sterility assurance level of at least 10⁻¹², e.g. byautoclaving (dwell time) at >121° C. for at least the 14-fold time ofthe D₁₂₁ value of the solution.
 37. A process according to claim 31, inwhich the container is depyrogenised before filling with thebisphosphonate solution, conveniently by washing with water, preferablyunder pressure.
 38. A process according to claim 31, in which anendotoxin/pyrogen-free or substantially endotoxin/pyrogen-free containeris obtained and is filled with the bisphosphonate solution.
 39. Aprocess according to claim 31, wherein the product comprises a non-ionicisotonising agent and in which ion chromatography, capillaryelectrophoresis, or high performance liquid chromatography (HPLC) isused for determination of the bisphophonate and its by- and degradationproducts
 40. A process according to claim 26, wherein the productcomprises a non-ionic isotonising agent and in which reversed phasechromatography, preferably with a complexation agent, e.g. EDTA, is usedfor determination of the bisphophonate and its by- and degradationproducts, advantageously with a limit of quantitation of at least 0.1%related to the declared dose, preferably without applying aderivatization step.